A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse

The central melanocortin system is critical for the long term regulation of energy homeostasis. Null mutations of the melanocortin-4 receptor (MC4-R) are associated with hyperphagia, obesity, and accelerated longitudinal grow th in mice and humans. However, little is known about the function of anoth er central melanocortin receptor, the MC3-R. To assess the role of the MC3- R in energy homeostasis, the majority of the mc3r coding sequence was delet ed from the mouse genome. In contrast to the MC4-R knockout, which exhibits increased food intake, increased somatic growth, and defects in metabolism , mc3r-/- mice exhibit an exclusively metabolic syndrome. Homozygous null m c3r mice, while not significantly overweight, exhibit an approximately 50% to 60% increase in adipose mass. Mc3r -/- mice also exhibit an unusual incr ease in respiratory quotient when transferred onto high fat chow, suggestin g a reduced ratio of fat/carbohydrate oxidation. Furthermore, male mc3r-/- mice also exhibit an approximately 50% reduction in locomotory behavior on the running wheel, suggesting reduced energy expenditure.